The Hedgehog Signaling Pathway: Where Did It Come From?

Complex body plans require sophisticated cell–cell signaling pathways. How these pathways evolved is often not very well understood. Here, we argue that the Hedgehog (Hh) signaling pathway may have arisen from systems that were originally designed for the transport and homeostasis of certain bacterial sterol analogs—the hopanoids. We propose a possible scenario for the evolution of Hh signaling and discuss how evolutionary considerations can shed light on the mysterious communication between the membrane-bound Hh transducers Patched (Ptc) and Smoothened (Smo). The importance of the Hh signaling pathway has long been documented, even in Greek mythology; the tale of the one-eyed Cyclops was likely inspired by rare birth defects related to reduced Hh signaling [1,2]. Whereas reduced Hh signaling can cause these and other developmental defects, inappropriate activation of Hh signaling contributes to certain forms of cancer, including basal cell carcinoma, the most commonly occurring form of skin cancer [3]. Both effects reflect the essential role of Hh in the control of patterning and growth during development and in the adult animal (for more detailed reviews, see [4–6]). The current model for the production, transport, and transmission of the Hh signal is summarized in Figure 1. Two important components acting at the cell membrane are Ptc, which is the likely receptor for Hh, and the seven-pass transmembrane protein Smo, which acts downstream of Ptc. In the absence of Hh, Ptc blocks Smo activity. How this repression is achieved, and subsequently overcome by the Hh ligand, remains a mystery. One key to solving it may lie in understanding the multiple connections of the Hh pathway to lipid metabolism (reviewed in [7]). In addition, we argue that evolutionary considerations can identify a possible scenario for the origin of Hh signaling. To begin addressing both aspects, we start with a detailed look at Ptc and Smo.